What was the most significant moment in the history of Ted and Zoey's relationship on How I Met Your Mother?

The most significant moment in the history of Ted and Zoey's relationship on How I Met Your Mother was when Ted chose to side with Zoey over his friends by supporting her in her fight to save The Arcadian building. This caused a rift in Ted's friendship with Marshall, who was representing the opposing side in the dispute. The situation eventually led to the end of Ted and Zoey's relationship, as their differing views on the matter proved to be irreconcilable.

Throughout the show, Ted had a history of getting invested in relationships that ultimately didn't work out, and his time with Zoey was no exception. However, their storyline served to show the challenges that can arise when two people have differing opinions on important issues, and how it can affect not just their relationship, but also their connections with those around them.